WO1992011869A1 - Anticorps monoclonaux specifiques du cd4 et ne provoquant pas la depletion, destines au traitement de diabete sucre insulinodependant (idmm) - Google Patents

Anticorps monoclonaux specifiques du cd4 et ne provoquant pas la depletion, destines au traitement de diabete sucre insulinodependant (idmm) Download PDF

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Publication number
WO1992011869A1
WO1992011869A1 PCT/GB1992/000074 GB9200074W WO9211869A1 WO 1992011869 A1 WO1992011869 A1 WO 1992011869A1 GB 9200074 W GB9200074 W GB 9200074W WO 9211869 A1 WO9211869 A1 WO 9211869A1
Authority
WO
WIPO (PCT)
Prior art keywords
depleting
treatment
insulin
diabetes mellitus
administration
Prior art date
Application number
PCT/GB1992/000074
Other languages
English (en)
Inventor
Anne Cooke
Herman Waldmann
Original Assignee
University College London
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University College London filed Critical University College London
Priority to JP50277792A priority Critical patent/JP3168005B2/ja
Priority to CA002100462A priority patent/CA2100462C/fr
Priority to DE69221605T priority patent/DE69221605T2/de
Priority to EP92902288A priority patent/EP0567490B1/fr
Priority to AU11647/92A priority patent/AU668081B2/en
Publication of WO1992011869A1 publication Critical patent/WO1992011869A1/fr
Priority to US08/436,843 priority patent/US5670150A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Non-depleting CD4-spec1f1c monoclonal an1t1bod1es for the treatment of insulin-dependent diabetes mellitus (IDDM) for the treatment of insulin-dependent diabetes mellitus (IDDM)
  • the present invention relates to the use of certain antibodies in the prevention and treatment of insulin- dependant diabetes ellitus.
  • Insulin-dependant diabetes mellitus (hereafter IDDM) is the juvenile-onset form of diabetes. At present there is no available cure for the disease and treatment consists of maintenance of insulin levels by oral or intramuscular administration and palliation of the inevitable side-effects both of the disease itself and of the treatments.
  • nd CD4 mAb a non-depleting CD4 monoclonal antibody
  • WO-A-90/15152 describes the use of nd CD4 mAbs in conjunction with non-depleting CD8 monoclonal antibodies in inducing tolerance to an antigen and suggests that this may be useful in surgery and therapy, for instance in preventing transplant rejection, treating autoimmune diseases and in avoiding undesirable immune reactions to peptide and hormone therapeutic agents. However this treatment is intended to block CD4 + and CD8 + cells and there is no indication that nd CD4 mAbs alone would be useful in any treatment.
  • the present invention provides a method for treating insulin-dependant diabetes mellitus comprising administering an effective, non-toxic amount of at least one non-depleting CD4 monoclonal antibody to a human or non-human patient in need thereof.
  • the term • 'antibody is intended to include any binding member having a binding domain which reacts with an epitope of the CD4 cell surface antigen.
  • the invention also covers derivatives and homologues of CD4 antibodies, fragments of antibodies containing at least one antigen binding site such as Fab and F(ab') 2 fragments and "single domain antibodies” also known as dAbs.
  • Monoclonal antibodies according to the invention are antibodies or fragments thereof produced by a clone of cells all derived from a single antibody-producing cell, which may have been obtained from a mammal immunised against the antigen recognised by the antibody or by transformation of a cell with expressible DNA encoding the antibody or fragment thereof, such DNA having been removed from a cell obtained from a mammal immunised against the antigen recognised by th antibody or constructed by recombinant techniques. Techniques of recombinant DNA technology may be used to produce antibodies or chimeric molecules with appropriate specificity for CD4.
  • Such techniques may involve introducin DNA encoding an immunoglobulin variable region, or one or more complementarity determining regions capable of binding CD4, to the constant regions, or constant regions plus framework regions, of a different immunoglobin, for example to convert a mouse-derived monoclonal antibody into one having largely human immunoglobulin characteristics (see EP 184187A, GB 2188638A) .
  • Another possibility is to attach jus the variable region of an antibody to another non- immunoglobulin molecule, to produce a chimeric molecule (see WO 86/01533) .
  • Yet another possibility would be to produce a mutation in the DNA encoding the monoclonal antibody, so as to alter certain of its characteristics without changing its essential specificity. This can be done by site-directed mutagenesis or other techniques known in the art. Monoclona antibodies and derivatives and homologues thereof and fragments thereof are produced by conventional techniques.
  • CD4 monoclonal antibody refers to a monoclonal antibody, or fragment thereof containing at least one antigen-binding site, capable of specifically binding an epitope of a CD4 cell surface antigen.
  • CD4 cell surface antigen includes the human CD4 cell surface antigen and corresponding cell surface antigens of other mammals such as the L3T4 antigen of mice.
  • non-depleting CD4 monoclonal antibody refers of CD4 monoclonal antibodies which deplete fewer than 50% of target cells jLn vitro.
  • Preferred nd CD4 mAbs deplete fewer than 25% and most probably less than 10% of target cells in vitro.
  • a simple test to ascertain wherein a CD4 mAb should be regarded as non-depleting is to take a sample of peripheral blood, count the target cells, ie CD4 + cells, in an aliquot as a control, treat a further aliquot with the CD4 mAb and count the target cells after treatment; if there are 50% or greater target cells in the treated aliquot compared with the control aliquot, the CD4 mAb is non-depleting in accordance with the invention.
  • nd CD4 mAbs may be obtained by conventional techniques for raising mAbs against CD4 and screening and selecting clones which secrete non- depleting antibodies.
  • Typically such antibodies will be of the IgG 2 class such as rat IgG 2a mouse IgG 2] _ j or human IgG 2 but human IgG 4 are also useful.
  • a preferred nd CD4 mAb for use in accordance with the present invention is YTS177.9 produced by a hybridoma deposited with the European Collection of Animal Cell Cultures under accession number ECACC 90053005 on 30th May 1990 in connection with International patent Application No PCT/GB90/00840.
  • nd CD4 mAbs for use in the present invention include nd CD4 mAb fragments of YTS 177.9 (ECACC 90053005) and nd CD4 mAbs and fragments thereof which have similar or higher affinity for the same epitope as YTS 177.9.
  • the treatment of diabetes patients in accordance with the present invention may commence in individuals identified as being at risk (for instance because of a family history of IDDM) prior to emergence of the disease but this is generally less preferred as it is believed that this will lead to a generalised tolerising of the patient to irrelevant antigens leading to a state of immunosuppression.
  • the treatment is commenced once the disease has become patent since at this stage loss of ⁇ -cells has already commenced and the treatment will then primarily interfere with the cause of the disease.
  • treatment will be commenced soon after the disease has become patent so that the patient will retain the majority of ⁇ -cells and, even if there is no regeneration of ⁇ -cells, insulin levels will be susceptible of management by conventional techniques but avoiding administration of insulin. Even when the disease has progressed to a late stage, the treatment will be beneficial in protecting the patient's remaining ⁇ -cells.
  • Treatment according to the invention comprises administration of at least one dose of nd CD4 mAb and preferably comprises a course of several doses.
  • the exact amount to be administered in any single dose and the number and timing of any subsequent doses will be determined by many factors including the age, sex, weight and size of the patient, the patient's general health and level of nutrition and the stage to which the patient's disease has progressed.
  • saturating amounts of the nd CD4 mAb will be most effective and that such amounts may be determined by routine pharmacokinetic studies; administration of greater than such amounts is uneconomic but unlikely to be harmful whereas administration of less than saturating amounts may also be effective but is likely to be less effective such that additional doses may be required.
  • doses of from l ⁇ g to 2mg, preferably from 400 ⁇ g to Img of nd CD4 mAb are administered.
  • doses of from 1 to 400 mg, such as from 3 to 30mg, for example from 5 to 20mg of nd CD4 mAb may be contemplated in an otherwise normal healthy adult of about 75kg.
  • Typical treatment regimes involve repeat doses being administered several times per week, for instance from 1 to 7 times per week, preferably from 1 to 4 times per week, for example 3 times per week and such regimes may continue for several weeks or even months, for instance for at least 2 weeks and up to 6 months, more preferably up to two months. It is presently envisaged that a single course of treatment will cure the disease for the lifetime of the patient but relapses and recurrences of the disease may be treated with further courses of treatment.
  • the nd CD4 mAbs are administered in accordance with the invention by conventional routes such as orally or parenterally, for instance by subcutaneous or intravascular, preferably intravenous, injection.
  • the nd CD4 mAbs are administered in the form of a composition comprising a pharmaceutically acceptable diluent or carrier.
  • Preferred compositions are pharmaceutical formulations for oral administration or for injection. Such formulations will generally comprise, in addition to a conventional diluent or carrier, suitable accessory ingredients.
  • the formulations may be presented in the form of tablets, capsules and other discrete dosage units or in multi-dose form such as bulk powders and liquids.
  • the formulations may be presented as solutions for injection, concentrated solutions to be diluted with a solvent for instance with pyrogen-free demineralised water or water for injection) prior to injection or as dry powders for dissolution in a solvent (for instance water for injection) prior to injection.
  • the accessory ingredients which will b selected according to the type of presentation, may be fillers, flavours, tabletting aids and coatings, preservatives, antioxidants, stabilisers, buffers, antimicrobial agents, surfactants, salts for adjusting tonicity and other conventional ingredients well known in the art of pharmacy.
  • the invention therefore provides a method as hereinbefore described consisting essentially of administering a single nd CD4 mAb species or a composition thereof.
  • the method consists of the administration of a composition of a single nd CD4 mAb species unaccompanied by administration of any CD8 mAb and unaccompanied by administration of any depleting mAb.
  • the present invention provides the use of a nd CD4 mAb in the preparation of a medicament for use in the treatment of IDDM in a human or non-human.
  • the medicament is a composition or pharmaceutical formulation as hereinbefore described.
  • the treatment will be as hereinbefore described, preferably using nd CD4 mAb YTS 177.9
  • Example 1 The invention will now be illustrated by the following Example which is not intended to limit the scope of protection in any way.
  • Example 1
  • the NOD mouse is considered by many to be a good model for IDDM since the spontaneous incidence among females is 60 to 80% by 30 weeks in most colonies. Among males, the incidence is much lower (for instance less than 10%) and this makes them an ideal recipient, when immunocompromised by irradiation, in which to induce disease by the transfer of spleen cells from diabetic donors.
  • YTS177 strongly protects NOD mice from IDDM transferred by diabetic donor spleen cells.
  • YTS177 is a non-depleting IgG 2a anti-CD4 rat monoclonal antibody which although recognising the same epitope as the depleting IgG 2j - ) monoclonal anti-CD4 YTS191.1 (ECACC 87072282) has a different mode of action since CD4 + T cells are not eliminated but appear to be permanently anergised.
  • mice Groups of 4 or 5 mice were irradiated using a cobalt source (650 rads per mouse) and spleen cells (2 x 10 7 per mouse) from diabetic donors were transferred intravenously the following day.
  • a control group (Group 1) received no antibody treatment.
  • Two groups of mice were treated with YTS177, given i.v. (2 mg per mouse) 3 days before transfer of spleen cells, and i.p. (2 mg per mouse on each occasion) on the next 2 days and then the same dose i.p. 3 times weekly for a total of 10 days following transfer of spleen cells (Group 3) or until sacrifice at week 4 (Group 2) .
  • the experiment was repeated for groups 1 and 2 only.
  • mice in Groups 1 and 2 were hyperglycaemic by week 4 compared with 7/9 control animals. Three months later all mice in Group 3 were still normoglycaemic.
  • Experiment 2 included a group of mice in which YTS177 treatment was delayed until 12 days after transfer of spleen cells when it was given i.v., i.p. and i.p. on 3 consecutive days and then 3 times weekly as before (Group 4) .
  • Groups 1 and 4 were repeated and administration of the depleting CD8 mAb (YTS169.4; ECACC 87072284) to a further group of mice (400 ⁇ g i.v., i.p. and i.p. on 3 consecutive days) starting 12 days after transfer of spleen cells was included for comparison (Group 5) .
  • Table 1 shows that no animal in Experiments 2,3 or 4 given YTS177 became diabetic whereas 9/13 untreated animals and 1/10 animals treated with depleting CD8 mAb were hyperglycaemic by week 5.
  • a further group of mice (Group 6) were given the depleting CD4 mAb (YTS191.1 ECACC 87072282) starting 12 days after transfer and any protection conferred on these animals was barely significant.
  • cryostat sections were prepared from the pancreata of Experiment 3 mice and stained for infiltrating T cells. Examination of pancreata from untreated mice sacrificed at day 12 after transfer revealed that peri-islet infiltration was already extensive with some intra-islet lymphocytes also present although the number of residual islets was still relatively low (23%) . Pancreata from animals given YTS177 from day 12 onwards and killed at 4 weeks after transfer were indistinguishable from the previous group (19% residual islets) suggesting that the antibody had arrested the infiltration and prevented any further ⁇ cell destruction. In contrast, the animals given no antibody treatment and killed at week 4 had extensive intra-islet infiltration and 70% of the islets were residual.
  • YTS177 is effective simply as a result of general immunosuppression, but when SRBC were administered i.p. to Group 4 mice two weeks after cessation of YTS177 treatment, or to a group of NOD mice irradiated and reconstituted with 2 x 10 7 normal spleen cells, the level of agglutinating anti-SRBC antibody found in the sera 5 days later, were comparable in both groups.
  • the protection afforded by antibody YTS177 was unexpectedly powerful when compared with the effect of monoclonal antibodies depleting either of the two major T cell subsets. In the case of the latter, it may be expected that newly emerging T cells will eventually be able to mount a response against ⁇ cells and any protection would thus be of limited duration.
  • the nd CD4 mAb by switching off ⁇ cell specific effectors and, perhaps, by initiating a protective idiotypic network, seems to offer permanent protection.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des anticorps monoclonaux de CD4, ne provoquant pas la déplétion, peuvent être utilisés pour le traitement du diabète sucré insulinodépendant.
PCT/GB1992/000074 1991-01-14 1992-01-14 Anticorps monoclonaux specifiques du cd4 et ne provoquant pas la depletion, destines au traitement de diabete sucre insulinodependant (idmm) WO1992011869A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP50277792A JP3168005B2 (ja) 1991-01-14 1992-01-14 病気の処置
CA002100462A CA2100462C (fr) 1991-01-14 1992-01-14 Anticorps monoclonaux anti-cd4 non depletifs pour le traitement du diabete sucre insulinodependant
DE69221605T DE69221605T2 (de) 1991-01-14 1992-01-14 Nicht-zellzahlverringernde cd4-spezifische monoklonale antikörper zur behandlung von insulinabhängigem diabetes mellitus (iddm)
EP92902288A EP0567490B1 (fr) 1991-01-14 1992-01-14 Anticorps monoclonaux specifiques du cd4 et ne provoquant pas la depletion, destines au traitement de diabete sucre insulinodependant (idmm)
AU11647/92A AU668081B2 (en) 1991-01-14 1992-01-14 Non-depleting CD4-specific monoclonal antibodies for the treatment of insulin-dependent diabetes mellitus (IDDM)
US08/436,843 US5670150A (en) 1991-01-14 1995-05-08 Non-depleting CD4-specific monoclonal antibodies for the treatment of insulin-dependent diabetes mellitus (IDDM)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9100741.9 1991-01-14
GB919100741A GB9100741D0 (en) 1991-01-14 1991-01-14 Treatment of disease

Publications (1)

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WO1992011869A1 true WO1992011869A1 (fr) 1992-07-23

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PCT/GB1992/000074 WO1992011869A1 (fr) 1991-01-14 1992-01-14 Anticorps monoclonaux specifiques du cd4 et ne provoquant pas la depletion, destines au traitement de diabete sucre insulinodependant (idmm)

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US (1) US5670150A (fr)
EP (1) EP0567490B1 (fr)
JP (1) JP3168005B2 (fr)
AT (1) ATE156711T1 (fr)
AU (1) AU668081B2 (fr)
CA (1) CA2100462C (fr)
DE (1) DE69221605T2 (fr)
ES (1) ES2106169T3 (fr)
GB (1) GB9100741D0 (fr)
WO (1) WO1992011869A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010009129A2 (fr) * 2008-07-15 2010-01-21 Genentech, Inc. Méthodes de traitement de maladies auto-immunes utilisant des anticorps cd4
EP3019193A4 (fr) * 2013-07-10 2017-03-15 The U.S.A. as represented by the Secretary, Department of Health and Human Services Induction de lymphocytes t régulateurs spécifiques d'antigènes, médiée par des cellules apoptotiques, pour le traitement de maladies auto-immunes chez l'homme et les animaux

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0708902A2 (pt) * 2006-03-16 2011-06-14 Genentech Inc mÉtodos de tratar lupus usando anticorpos cd4
KR20190120987A (ko) * 2018-04-17 2019-10-25 국립암센터 고갈성 항 cd4 단일클론항체를 포함하는 항암 t 세포치료제 보조용 조성물 및 이의 용도

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69020914T2 (de) * 1989-01-23 1996-03-07 Abbott Lab Monoklonale Antikörper von Ratten gegen menschliche Antigene und Verfahren zu deren Herstellung.
GB8912497D0 (en) * 1989-05-31 1989-07-19 Cobbold Stephen P Monoclonal antibodies

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Autoimmunity, vol. 4, nos. 1-2, 1989, (GB), B. CHARLTON et al.: "Recurrence of insulitis in the NOD mouse after early prolonged anti-CD4 monoclonal antibody treatment", pages 1-7, see the whole document *
Clinical Immunology and Immunopathology, vol. 56, no. 3, September 1990, (New York, US), N.L. CARTERON et al.: "F(ab')2 anti-CD4 and intact anti-CD4 monoclonal antibodies inhinit the accumulation of CD4+ T cells, CD8+ T cells, and B cells in the kidneys of lupus-prone NZB/NZW mice", pages 373-383, see the whole document *
Journal of the Japan Diabetes Society, vol. 30, no. 1, 1987, (Tokyo, JP), Y. ITOH et al.: "Studies of type I diabetes in NOD mice. Treatment of NOD mice with monoclonal antibody to L3T4", pages 47-49, see the abstract *
Transplantation Proceedings, vol. 22, no. 5, October 1990, (New York, US), M. KOULMANDA et al.: "Prolongation of fetal pancreas allograft survival in mice treated with anti-IL-2 receptor monoclonal antibocy (PC61) conjugated with idarubicin", pages 2113-2114, see the whole document *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010009129A2 (fr) * 2008-07-15 2010-01-21 Genentech, Inc. Méthodes de traitement de maladies auto-immunes utilisant des anticorps cd4
WO2010009129A3 (fr) * 2008-07-15 2010-05-06 Genentech, Inc. Méthodes de traitement de maladies auto-immunes utilisant des anticorps cd4
EP3019193A4 (fr) * 2013-07-10 2017-03-15 The U.S.A. as represented by the Secretary, Department of Health and Human Services Induction de lymphocytes t régulateurs spécifiques d'antigènes, médiée par des cellules apoptotiques, pour le traitement de maladies auto-immunes chez l'homme et les animaux

Also Published As

Publication number Publication date
EP0567490B1 (fr) 1997-08-13
DE69221605T2 (de) 1998-02-12
CA2100462C (fr) 2003-06-17
AU1164792A (en) 1992-08-17
JP3168005B2 (ja) 2001-05-21
AU668081B2 (en) 1996-04-26
ES2106169T3 (es) 1997-11-01
EP0567490A1 (fr) 1993-11-03
ATE156711T1 (de) 1997-08-15
JPH06504283A (ja) 1994-05-19
CA2100462A1 (fr) 1992-07-15
DE69221605D1 (de) 1997-09-18
US5670150A (en) 1997-09-23
GB9100741D0 (en) 1991-02-27

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